It takes too many healthy volunteers and too many years to evaluate promising presymptomatic Alzheimer's disease (AD) treatments, interventions intended to reduce the risk of AD symptoms or prevent them completely, using clinical endpoints. While AD biomarkers are needed to rapidly evaluate the range of promising presymptomatic AD treatments, regulatory agencies are unlikely to qualify them for use as surrogate endpoints under their accelerated approval provisions until randomized clinical trials (RCTs) clarify the extent to which the biomarkers respond to AD-modifying treatments and are reasonably likely to predict a clinical benefit. The Alzheimer's Prevention Initiative (API) is intended to help accelerate the evaluation of promising presymptomatic AD treatments and find ones that work as soon as possible. This application seeks five years of partial support for the first stage of a multi-center, randomized, placebo-controlled, adaptive-design trial. This initial 104 week trial is of an investigational amyloid-modifying treatment for 200 cognitively normal, autosomal- dominant early-onset AD (EOAD) mutation carriers (and 100 matched placebo-treated non-carriers) who are within 15 years of their estimated age at clinical onset. An adaptive element uses serial futility analyses and an interim analysis at 104 weeks for a study continuation decision. Outcomes include the best established brain imaging and cerebrospinal fluid (CSF) biomarkers of AD and a sensitive composite cognitive endpoint. Most participants will be presenilin 1 (PS1) E280A mutation carriers and placebo-treated non-carriers from the world's largest, known EOAD kindred in Antioquia, Colombia. US participants are included to share opportunities and risks with the Colombian volunteers. This is an extremely inclusive project, having been vetted by leading academic and community stakeholder advisors, and representatives from the NIA, FDA, European Medicines Agency, and pharmaceutical research companies. One third of the funding is requested from the NIA, contingent upon pharmaceutical industry and Banner Alzheimer's Foundation commitments for the remaining funds, ensuring that the data and biological samples are available to the public upon study completion to further develop the biomarkers needed to rapidly evaluate presymptomatic treatments in other populations and trials. To help launch a new era in AD prevention research, the project aims to (1) conduct the first stage of an RCT of an investigational amyloid-modifying treatment in presymptomatic EOAD mutation carriers, (2) determine the extent to which the treatment's biomarker effects at week 104 predict subsequent clinical effect, (3) determine the extent to which the biomarkers are prognostic or predictive of AD, (4) compare baseline and longitudinal measurements in mutation carrier and non-carrier placebo treatment groups, (5) provide almost 1,000 mutation carriers and a public resource of data and biological samples as soon as possible after the trial is completed, and (6) complement and support other important programs (e.g., in the DIAN, ADCS, ADNI and a US-based API Registry and an RCT in APOE 4 homozygotes and heterozygotes). PUBLIC HEALTH RELEVANCE: It currently takes too many people, too much money, and too many years to evaluate Alzheimer's disease (AD) prevention therapies. The Alzheimer's Prevention Initiative (API) is intended to start evaluating promising experimental treatments in people who, based on their genetic background and age, are at the highest imminent risk of development the memory and thinking problems associated with AD-including members from the world's largest extended family of early-onset AD mutation carriers in Medellin, Colombia. The API is intended to help establish the biological measurements and accelerated FDA approval pathway needed to rapidly evaluate promising prevention therapies and find ones that work as quickly as possible.